The mammalian CNS contains an abundant, widely distributed population of glial progenitors known as NG2 cells (also termed oligodendrocyte precursor cells or polydendrocytes) that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although these cells retain the capacity to generate oligodendrocytes in the adult brain and spinal cord, most NG2 cells in the adult CNS do not differentiate and remain in a "progenitor" state. NG2 cells are arranged in a grid-like manner in all gray and white matter regions, extend highly ramified processes into the surrounding neuropil, and form direct synapses with neurons, raising the possibility that they modulate the activity of neurons and the flow of information through neural circuits. Moreover, NG2 cells proliferate, increase expression of NG2, and contribute to the formation of glial scars in response to both acute and chronic injury, suggesting that they may help limit neurodegeneration and promote repair. Nevertheless, our knowledge about the roles of these abundant glial cells, and the consequences of their change in behavior following ischemic injury, is very limited. To define the functions of NG2 cells in the adult brain, we recently developed transgenic mice that allow selective ablation of NG2 cells in vivo. Using these mice, NG2 cells can be removed from the brain without inducing reactive changes in astrocytes or microglial cells, or causing paralysis or death, indicating that this approach can be used to help define the functions of these ubiquitous glial cells. In the proposed studies, we will selectively ablate NG2 cells from the CNS in vivo, and examine whether their absence results in alterations in neuronal activity, signaling at synapses, axonal conduction, or specific aspects of behavior, such as spatial memory, anxiety, or sensorimotor control. In addition, we will examine whether removal of NG2 cells alters the response of other glial cells to focal ischemia and the extent of neuronal injury. Together, these exploratory studies have the potential to reveal new roles for this enigmatic population of glial cells in the adult brain, and deepen our understanding of interactions that occur between neurons and glial cells in physiological and pathological conditions. If NG2 cells participate in neuromodulation and CNS repair, they would represent an additional therapeutic target with the potential to reduce abnormal neuronal activity, prevent neurodegeneration in chronic disease, and promote recovery and repair following stroke. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine whether an abundant, widely distributed population of glial cells in adult CNS influences the flow of information through neural circuits and promotes repair following ischemia. These studies have the potential to identify new pathways for regulating abnormal neuronal activity, as well as reducing injury and accelerating recovery after stroke.